Nephrol Dial Transplant (1998) 13: 867–874
Nephrology
Dialysis
Transplantation
Molecular Basis of Renal Disease
Mechanisms and clinical significance of cell volume regulation
Siegfried Waldegger1, Silvia Steuer2, Teut Risler2, August Heidland3, Giovambattista Capasso4,
Shaul Massry5 and Florian Lang1
Departments of 1Physiology and 2Internal Medicine, University of Tübingen, 3Kuratorium für Nephrologie, Würzburg,
Germany, 4Department of Nephrology, Second University of Napoli, Italy and 5Division of Nephrology, University of
Southern California, Los Angeles, CA
Abstract
A wide variety of factors challenge constancy of cell
volume. Alterations of cell volume activate diverse cell
volume regulatory mechanisms including ion transport,
osmolyte accumulation, metabolism and expression of
appropriate genes. A wealth of cellular signalling pathways link cell volume to the respective regulatory
mechanisms. Cell volume emerges as a pathophysiologically important parameter in several diseases including
diabetes mellitus, uraemia, hepatic insufficiency and
hypercatabolic states. The role of altered cell volume
in disease is a challenge which requires more experimental research and clinical investigation.
Introduction
One of the most important tasks of the kidney is to
finely tune water and electrolyte composition of the
body. Without appropriate water and electrolyte
homeostasis constancy of body compartments cannot
be achieved. Thus, failure of the kidney adequately to
regulate water and electrolyte excretion must eventually lead to alterations of extracellular and/or
intracellular volumes.
While a great deal of information has been gathered
on causes and sequelae of deranged extracellular
volume homeostasis, the pathophysiology of cellular
volume homeostasis has remained less understood.
Even at constant extracellular osmolarity a wide
variety of mechanisms challenge cell volume homeostasis and a similar diversity of mechanisms serve to
maintain a constant cell volume. Beyond that alterations of cell volume profoundly influence a number of
cellular functions not obviously related to cell volume.
We provide a brief discussion of the challenges of
cell volume constancy, cell volume regulatory mechanisms and cell volume-sensitive functions as well as
Correspondence and offprint requests to: Prof. Dr F. Lang,
Physiologisches Institut, Universität Tübingen, Gmelinstrasse 5,
D-72076 Tübingen, Germany.
some examples illustrating the participation of
deranged cell volume regulation in disease states. For
a more extensive treatment of cell volume regulatory
mechanisms and the functional significance of cell
volume the reader is referred to previous reviews [1–3].
Challenges of cell volume constancy
With only few exceptions, cell membranes are highly
permeable to water [4]. In general, water movement is
driven by an osmotic and a hydrostatic pressure gradient. However, animal cell membranes do not withstand
significant hydrostatic pressure gradients and water
movement is determined by osmotic gradients across
the cell membrane. To avoid alterations of cell volume,
cells have to maintain osmotic equilibrium across the
cell membrane. Excess intracellular osmolarity will lead
to entry of water and thus cell swelling, whereas excess
extracellular osmolarity will abstract water from the
cells and thus lead to cell shrinkage.
Since cells accumulate osmotically active substrates,
such as amino acids and carbohydrates, they must
decrease intracellular electrolyte concentration to
achieve osmotic equilibrium across the cell membrane
[5]. To this end cells extrude Na+ in exchange for K+
by the Na+/K+ ATPase. Usually the cell membrane is
poorly permeable to Na+ but highly permeable to K+.
According to the chemical gradient K+ tends to exit
the cell through K+ channels creating a cell-negative
potential difference across the cell membrane. This cell
membrane potential drives exit of anions such as Cl−.
As a result, Cl− is some 80 mM lower within as
compared to outside of the cell, thus establishing
osmotic equilibrium. As long as the cell membrane is
not perfectly impermeable to Na+, the maintenance of
a constant cell volume requires expenditure of energy
to fuel the operation of Na+/K+ ATPase. As described
later in this review, energy depletion will eventually
lead to cell swelling.
Constancy of cell volume is further challenged by
ion channel activation. Activation of Na+ channels
depolarizes the cell membrane and thus favours simul-
© 1998 European Renal Association–European Dialysis and Transplant Association
868
taneous entry of Cl−. The cellular accumulation of
NaCl leads to cell swelling. On the other hand, activation of K+ and/or Cl− channels will favour KCl exit
and results in cell shrinkage. The channels are activated
by a wide variety of mediators. Glutamate, for instance,
swells some cells by activation of Na+ channels [6 ]
and acetylcholine shrinks cells by activation of K+
and Cl− channels [7].
Increase of extracellular K+ concentration decreases
the chemical driving force for K+ exit, depolarizes the
cell membrane and thus favours cellular KCl accumulation and cell swelling [2].
Activation of Na+, K+, 2Cl− co-transport leads to
cellular uptake of NaCl and KCl and thus to cell
swelling. Stimulation of Na+/H+ exchange leads to
entry of Na+ and intracellular alkalosis which in turn
stimulates Cl−/HCO− exchange. The tandem leads
3
to NaCl accumulation, since H+ and HCO− are
3
replenished within the cells from CO (or H CO ,
2
2 3
respectively) which readily permeates across the cell
membrane [3]. Na+, K+, 2Cl− co-transport and
Na+/H+ exchange are activated by insulin [8–10] and
a wide variety of growth factors [11], which thus lead
to cell swelling. Glucagon and cAMP shrink hepatocytes by stimulation of ion channels [8,9].
Organic acids, such as lactate may enter the cell in
the non-dissociated moiety, dissociate within the cell
and thus create intracellular acidosis. H+ ions are then
extruded by the Na+/H+ exchanger and the cells swell
due to accumulation of Na+ and the acid anion [2].
Na+-coupled concentrative uptake of substrates
such as amino acids or glucose leads to depolarization,
parallel entry of Cl− and cell swelling due to accumulation of NaCl and the substrates [12,13].
On the one hand breakdown of proteins, glycogen
or triglycerides, which are osmotically less active than
the sum of their constituent parts leads to an increase,
on the other hand release of substrates and formation
of proteins, glycogen or triglycerides to a decrease of
intracellular osmolarity.
Obviously, alterations of extracellular osmolarity
challenge cell volume constancy and clinical conditions
with hypo- or hypernatraemia may be associated with
cell swelling and cell shrinkage respectively, as outlined below.
S. Waldegger et al.
(a)
Cell volume regulatory mechanisms
(b)
Alterations of cell volume trigger a variety of cellular
mechanisms aiming at re-establishing the set point of
cell volume. Among these, ion transport across the cell
membrane is the most rapid and efficient mechanism
of adjusting cellular osmolarity.
Fig. 1. Cell volume regulatory mechanisms. (A) Mechanisms
increasing cell volume following cell shrinkage: Parallel activation
of Na+/H+ exchanger and Cl−/HCO− exchanger (a); Na+, K+,
3
2Cl− cotransport (b); NaCl cotransport (c); Na+ channels and
Na+/K+ ATPase (d); inhibition of K+- and Cl− channels (e);
cellular accumulation of glycerophosphorylcholine by inhibition of
phosphodiesterase (f ), Na+ coupled accumulation of inositol, taurine and betaine (g); cellular accumulation of sorbitol by activation
of aldosereductase (h). (B) Mechanisms decreasing cell volume
following cell swelling: Activation of K+ and anion channels (a);
activation of KCl cotransport (b); activation of Na+/Ca++
exchanger and Ca++ ATPase (c); parallel activation of K+/H+
exchange and Cl−/HCO− exchange (d); release of osmolytes, such
3
as sorbitol, inositol, taurine, betaine (e); Na+ ATPase (f ); inhibition
of Na+ channels (g).
Cell volume regulatory ion transport
Following cell swelling, cells have to release ions to
reduce their osmolarity. In most cells ion release is
accomplished by activation of K+ channels and/or
anion channels ( Figure 1). A great diversity of distinct
Cell volume regulation
ion channels has been shown to serve volume regulation in different cells. Other transport processes mediating cellular loss of electrolytes include KCl symport,
parallel K+/H+ exchange and Cl−/HCO− exchange
3
( leading to KCl loss) as well as Na+/Ca2+ exchange
in parallel to Ca2+ ATPase ( leading to loss of Na+) [3].
Following cell shrinkage, cells accumulate ions
through activated Na+, K+, 2Cl− cotransport and/or
Na+/H+ exchange together with Cl−/HCO− exchange
3
(see above). The Na+ thus accumulated is replaced by
K+ via the Na+/K+ ATPase. The transporters thus
mediate eventually uptake of KCl. Shrunken cells
avoid further ion loss by inhibition of K+ and/or Cl−
channels [3].
Osmolytes
The use of ions as osmolytes is limited, since high ion
concentrations interfere with the stability of proteins.
Moreover, alterations of intracellular Na+ activity
could increase intracellular Ca2+ activity via reversal
of Na+/Ca2+ exchange, and the stimulation of
Na+/H+ exchange in shrunken cells usually results in
cellular alkalinization. Altered intracellular pH and
Ca2+ concentration in turn affect a multitude of cellular functions.
To avoid the effects of altered ion concentrations,
most cells utilize so called compatible osmolytes, i.e.
organic substances specifically designed to create
intracellular osmolarity without destabilizing proteins
[14–17]. The most important osmolytes are polyols
such as sorbitol and myoinositol, the amino acid
taurine and methylamines, such as betaine and glycerophosphorylcholine.
Glycerophosphorylcholine (GPC ) formation from
phosphatidylcholine is catalysed by a phospholipase
A other than the arachidonyl selective enzyme, and is
2
degraded by a phosphodiesterase to glycerol-phosphate
and choline. Increase of extracellular osmolarity
inhibits the phosphodiesterase and thus leads to accumulation of GPC. Sorbitol is produced from glucose
by an aldose reductase. Osmotic cell shrinkage stimulates the transcription rate of the aldose reductase.
Myoinositol (inositol ), betaine and taurine are accumulated by specific Na+-coupled transporters. Osmotic
cell shrinkage stimulates the transcription rate of the
transport molecules. Similarly, some amino acids are
accumulated into shrunken cells by stimulation of
Na+-coupled transport.
Upon cell swelling GPC, sorbitol, inositol, betaine
and taurine are rapidly released through poorly defined
transport systems (for review see Lang et al. [2,3]).
869
proteolysis and glycogenolysis [13,18–26 ]. The amino
acids and glucosephosphate are thus incorporated into
the osmotically less active macromolecules. The effect
of cell volume on protein metabolism is exploited by
hormones such as insulin and glucagon ( Figure 2). As
a matter of fact, the antiproteolytic effect of insulin
and the proteolytic effect of glucagon in the liver is
exclusively the result of the respective swelling or
shrinking effect of the hormones [8–10].
A number of further metabolic pathways have been
shown to be sensitive to cell volume. Cell swelling
inhibits glycolysis and stimulates flux through the
pentose phosphate pathway, NADPH production
[27,28], glutathione (GSH ) formation and efflux into
blood [29], glycine oxidation [30], glutamine breakdown [12], formation of NH+ and urea from amino
4
acids [31], ketoisocaproate oxidation [30] as well as
lipogenesis from glucose [32]. The mRNA for phosphoenolpyruvate carboxykinase, a key enzyme for
gluconeogenesis, is decreased by cell swelling [33].
Signalling
Alterations of cell volume influence a myriad of cellular
signalling molecules which in turn trigger the cell
volume regulatory machinery.
Cell swelling may lead to increase of intracellular
Ca2+ activity by cellular release triggered by 1,4,5inositoltrisphosphate and/or Ca2+ entry through Ca2+
channels in the plasma membrane [34].
Cell volume changes modify the architecture of the
cytoskeleton and the expression of cytoskeletal proteins
[35,36 ]. Conversely, cytoskeletal elements participate
Other metabolic pathways sensitive to cell volume
Cell shrinkage stimulates the breakdown of proteins
and of glycogen to amino acids and glucosephosphate,
respectively, which are osmotically more active than
the macromolecules. Cell shrinkage inhibits protein
and glycogen synthesis. Conversely, cell swelling stimulates protein and glycogen synthesis and inhibits
Fig. 2. Effect of insulin and of glucagon on cell volume. Insulin
swells cells by KCl uptake via activation of Na+/H+ exchange,
Na+, K+, 2Cl−-cotransport and Na+/K+ ATPase. Glucagon shrinks
cells by activation of K+- and anion channels. The cell volume
changes participate in the signalling of hormone action. For instance,
the antiproteolytic effect of insulin and the proteolytic effect of
glucagon completely depend on the hormone induced alterations of
cell volume.
870
S. Waldegger et al.
Fig. 3. Cell volume regulated gene expression. Cell volume influences the expression of a variety of genes. It does so in part through
osmoresponsive or cell volume responsive elements (CVRE ). Genes sensitive to cell volume encode for carriers, cytoskeletal elements,
enzymes and signaling molecules. The insert demonstrates the upregulation of the serine/threonine kinase h-sgk by increase of medium
osmolarity.
in the triggering of cell volume regulatory mechanisms
[33,37–39].
Both cell swelling and cell shrinkage modify the
phosphorylation of a variety of proteins, kinases
reported to be activated by cell swelling include
tyrosine kinases, protein kinase C, adenylate cyclase,
MAP kinase, Jun-kinase, and focal adhesion kinase
(p121FAK ) [1].
Osmotic cell shrinkage has been postulated to activate protein kinase C or a similar kinase. As a matter
of fact, cell shrinkage increases the expression of the
serine/threonine kinase h-sgk (human serum and glucocorticoid-dependent kinase) [40]. The targets of this
kinase, however, have not been identified yet.
Cell swelling activates a phospholipase A , leading
2
to formation of the 15-lipoxygenase product
hepoxilin A and the 5-lipoxygenase product leukotri3
ene LTD [1]. These eicosanoids are thought to trigger
4
cell volume regulatory K+ and/or Cl− channels and/or
volume regulatory taurine release. The enhanced
formation of leukotrienes may parallel a decreased
formation of PGE leading to inhibition of PGE 2
2
sensitive Na+ channels. On the other hand, PGE may
2
activate volume regulatory K+ channels in other cells
[2].
Cell swelling alkalinizes acidic cellular compartments, whereas cell shrinkage enhances the acidity in
these compartments [37,41,42]. In hepatocytes, this
effect may contribute to the antiproteolytic action of
cell swelling since lysosomal proteases are known to
have acidic pH optima and lysosomal alkalinization is
known to inhibit proteolysis [43]. Experiments in other
cells such as pancreatic b cells and neurons demonstrate
that cell swelling alkalinizes similarly secretory granules [44,45].
Cell volume influences the expression of several
genes (Figure 3). As indicated above, cell shrinkage
stimulates expression of enzymes or transporters
accomplishing cellular formation or accumulation of
osmolytes, such as the aldose reductase, and the Na+coupled transporters for betaine, taurine, inositol and
amino acids as well as Na+, K+, 2Cl− co-transport.
The enhanced expression of the cell volume regulated
kinase h-sgk possibly triggers mechanisms of regulatory cell volume increase. Other genes preferably
expressed in shrunken cells include ClC-K1, P-glycoprotein, heat shock proteins, the immediate early genes
Egr-1 and c-fos, cycloxygenase-2, phosphoenolpyruvate carboxykinase (PEPCK ), tyrosine aminotransferase, aB crystallin, laminin B and matrix proteins.
2
Genes expressed preferably in swollen cells include bactin, tubulin, immediate early gene c-jun, ornithine
decarboxylase, arginine succinate lyase and tissue
plasminogen activator [2,46 ].
Pathophysiology of cell volume
Energy depletion
Constancy of cell volume is compromised by energy
depletion, which will dissipate the Na+ and K+ gradients, lead to depolarization and cellular accumulation
of Cl− ( Figure 4). Furthermore, an increasing extracel-
Cell volume regulation
871
Fig. 4. Cell swelling by energy depletion. The Na+/K+ ATPase maintains a low intracellular Na+ and high intracellular K+. K+ diffusion
along the chemical gradient establishes a cell membrane potential (PD) which drives Cl− out of the cells (A). Energy depletion compromizes
the function of the Na+/K+ ATPase, and thus leads to dissipation of Na+ and K+ gradient, depolarization, entry of Cl− and subsequent
cell swelling (B).
lular K+ concentration will depolarize the cell membrane leading to Cl− accumulation [47]. The cell
swelling during anoxia is compounded by the formation of lactate, cellular acidosis and enhanced Na+/H+
exchange activity (see above). In neuronal tissue, the
depolarization triggers the release of glutamate and
the subsequent opening of unspecific cation channels
results in further cell swelling [2,47].
Cell proliferation and apoptotic cell death
Growth promoters are well known stimulators of
Na+/H+ exchange and some growth factors have been
described to stimulate Na+, K+, 2Cl− co-transport
[11,48]. Similarly, ras oncogene, which allows growth
factor independent cell proliferation has been shown
to shift the set point for cell volume regulation towards
greater cell volume [11,49]. Activation of Na+/H+
exchange leads in addition to cellular alkalinization
[50–53] and cell swelling to an increase of pH in
lysosomes of proliferating cells [54]. Cell volume
increase and subsequent alkalinization of lysosomal
pH may account for the antiproteolytic action of
growth factors, such as TGF-b1.
One of the hallmarks of apoptotic cell death is cell
shrinkage. Indeed, marked osmotic cell shrinkage
(>30%) has been shown to trigger apoptotic cell death.
However, a moderate decrease of cell volume (<30%)
rather blunts receptor triggered apoptotic cell death,
since it interferes with cellular O− formation which is
2
an important element of the signalling cascade leading
to receptor-mediated apoptotic cell death [2].
Hyponatraemia—hypernatraemia
A wide variety of conditions lead to altered extracellular Na+ concentration. While hypernatraemia is always
associated with enhanced extracellular osmolarity [55],
hyponatraemia may be paralleled by decreased, normal
or even increased extracellular osmolarity, such as in
diabetes mellitus [56 ]. To the extent that the altered
Na+ concentrations reflect altered extracellular osmolarity, they trigger cell volume regulatory mechanisms.
The changes of extracellular osmolarity are most critical for the function of the brain which cannot expand
significantly within the rigid skull. Furthermore, in
brain cell volume regulation by altered ion transport
would compromize neuronal function. Thus, the brain
is dependent on osmolytes for adequate cell volume
regulation in anisotonic conditions. The osmolyte
formation and disposal are relatively slow processes,
requiring days. Rapid development of hypernatraemia
or hyponatraemia as well as rapid correction of longstanding anisotonic conditions may thus lead to
decompensation and neuronal catastrophy [57–60].
Hepatic encephalopathy
The impaired urea formation in liver insufficiency leads
to accumulation of NH which enters the brain and is
3
taken up by glial cells. NH stimulates cellular forma3
tion and accumulation of glutamine which leads to cell
swelling [61,62]. As a matter of fact, a decrease of the
osmolyte inositol has been observed in patients with
liver insufficiency [63,64]. It is thought that the subsequent impairment of glial function contributes to the
development of encephalopathy.
Diabetes mellitus
The hyperglycaemia of diabetes mellitus enhances the
formation of sorbitol from glucose, the subsequent
excessive cellular accumulation of sorbitol has been
postulated to cause cell swelling which should account
872
for a variety of diabetic complications [65]. Moreover,
advanced glycosylation end products may via an as
yet unknown mechanism swell cells and thus inhibit
protein degradation [66 ]. On the other hand, intriguing
evidence has been gathered for cell shrinkage in
hyperosmolar diabetes mellitus which, through altered
cellular Ca2+ concentration, is thought to create cell
damage [67]. Clearly, more information is needed to
clarify the role of cell swelling and shrinkage in the
genesis of diabetic complications.
Chronic renal failure and uraemia
Cell volume changes may contribute to the progression
of renal failure: TGF-b1 is thought to further renal
fibrosis at least in part by inhibition of proteolysis
[68,69]. The antiproteolytic action of TGF-b1 has been
shown to be at least partially due to the swelling effect
of this growth factor. In insulin dependent diabetes
mellitus, the cell volume of fibroblasts corelated with
progression of renal disease [70]. Presumably the larger
fibroblasts display increased formation of extracellular matrix.
Urea destabilizes proteins and thus modifies the cell
volume regulatory set point. Urea has been shown to
shrink a number of cells, including erythrocytes, hepatocytes, renal cells and vascular smooth muscle cells
[71–73]. The cell shrinkage may then affect a variety
of cellular functions. In uraemia however, the perturbing effect of urea is probably counteracted by
enhanced availibility of methylamines which exert a
stabilizing effect on proteins [74]. Nevertheless, rapid
alterations of urea concentration, as they occur during
dialysis, are expected to disturb the balance of stabilizing osmolytes and destabilizing urea.
Hypercatabolic states
In hypercatabolic states, such as burns, acute pancreatitis, severe injury, liver carcinoma, a striking correlation was found between muscle cell volume and urea
excretion. In view of the profound stimulatory effect
of cell shrinkage on proteolysis a causal role of altered
cell volume in these hypercatabolic states has been
suggested [22]. At this point we do not know whether
the muscle cell shrinkage is paralleled by similar shrinkage of other cells including liver nor do we know the
mechanisms accounting for cell shrinkage in those
patients. However, the effect of cell volume on proteolysis is certainly not restricted to the liver and the
alterations of cell shrinkage is likely to be an important
pathophysiological mechanism in hypercatabolic
states. Along these lines, hypercatabolism can be counteracted by glutamine, which, at least in liver, leads to
profound cell swelling [12].
Conclusions
Alterations of cell volume or hydration influence a
myriad of cellular functions including transport, metabolism and gene expression. Compelling evidence indi-
S. Waldegger et al.
cates that perturbations of cell volume participate in
the pathophysiology of a wide variety of diseases. It is
hoped that this review enhances the perception for
alterations of cell volume in clinical conditions and
thus stimulates further research on the pathophysiological role of cell hydration.
Acknowledgements. Research in the authors laboratories has been
supported by the DFG (La 315/4-3), the EU (contract number
ERBCHRXCT 94-0595), the Baxter Foundation and the BMWFT
(IKFZOIKS9602).
References
1. Hoffmann EK, Dunham PB. Membrane mechanisms and
intracellular signalling in cell volume regulation. Int Rev Cytol
1995; 161: 173–262
2. Lang F, Busch GL, Ritter M, Völkl H, Waldegger S,
Häussinger D. The functional significance of cell volume. Physiol
Rev 1998; 78: 1–60
3. Lang F, Busch GL, Völkl H, Waldegger S. The diversity of cell
volume regulatory mechanisms. Cell Physiol Biochem 1998;
8: 1–45
4. MacKnight ADC. Principles of cell volume regulation. Renal
Physiol Biochem 1988; 11: 114–141
5. Lang F, Völkl H, Häussinger D. General principles in cell
volume regulation. In: Beyenbach KW, ed. Cell volume regulation, Karger-Verlag, Basel: 1990; 1–25
6. Choi DW. Glutamate neurotoxicity and diseases of the central
nervous system. Neuron 1988; 1: 623–634
7. Nauntofte B. Regulation of electrolyte and fluid secretion in
salivary acinar cells. Am J Physiol 1992; 263 (6 Pt 1): G823–G837
8. Vom Dahl S, Hallbrucker C, Lang F, Gerok W, Häussinger D.
Regulation of liver cell volume and proteolysis by glucagon and
insulin. Biochem J 1991; 278: 771–777
9. Vom Dahl S, Hallbrucker C, Lang F, Häussinger D. Regulation
of cell volume in the perfused rat liver by hormones. Biochem J
1991; 280: 105–109
10. Hallbrucker C, vom Dahl S, Lang F, Gerok W, Häussinger D.
Inhibition of hepatic proteolysis by insulin. Role of hormoneinduced alterations of the cellular K+ balance. Eur J Biochem
1991; 199: 467–474
11. Ritter M, Woell E. Modification of cellular ion transport by the
ha-ras oncogene: Steps towards malignant transformation. Cell
Physiol Biochem 1996; 6: 245–270
12. Häussinger D, Lang F, Bauers K, Gerok W. Interactions
between glutamine metabolism and cell volume regulation in
perfused rat liver. Eur J Biochem 1990; 188: 689–695
13. Häussinger D, Hallbrucker C, vom Dahl S, Decker S,
Schweizer U, Lang F, Gerok W. Cell volume is a major
determinant of proteolysis control in liver. FEBS Lett 1991;
283: 70–72
14. Garcia-Perez A, Burg MB. Renal medullary organic osmolytes.
Physiol Rev 1991; 71: 1081–1115
15. Wolff SD, Balaban RS. Regulation of the predominant renal
medullary organic solutes in vivo. Annu Rev Physiol 1990;
52: 727–746
16. Kinne RKH, Czekay R-P, Grunewald JM, Mooren FC, KinneSaffran E. Hypotonicity-evoked release of organic osmolytes
from distal renal cells: Systems, signals, and sidedness. Renal
Physiol Biochem 1993; 16: 66–78
17. Beck FX, Dörge A, Thurau K, Guder WG. Cell osmoregulation
in the countercurrent system of the renal medulla: the role of
organic osmolytes. In: Cell volume regulation, Beyenbach KW,
ed. Karger; Basel Suisse, 1990: 132–158
18. Baquet A, Hue L, Meijer AJ, van Woerkum GM, Plomp PJAM.
Swelling of rat hepatocytes stimulates glycogen synthesis by
insulin. J Biol Chem 1990; 265: 955–959
19. Häussinger D, Lang F. Cell volume: a ‘second messenger’ in the
regulation of metabolism by amino acids and hormones. Cell
Physiol Biochem 1991; 1: 121–130
20. Häussinger D, Lang F. Cell volume in the regulation of hepatic
Cell volume regulation
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
38.
39.
40.
41.
42.
function: a potent new principle for metabolic control. Biochim
Biophys Acta 1991; 1071: 331–350
Häussinger D, Hallbrucker C, vom Dahl S, Lang F, Gerok W.
Cell swelling inhibits proteolysis in perfused rat liver. Biochem
J 1990; 272: 239–242
Häussinger D, Roth E, Lang F, Gerok W. Cellular hydration
state: an important determinant of protein catabolism in health
and disease. Lancet 1993; 341: 1330–1332
Hallbrucker C, vom Dahl S, Lang F, Häussinger D. Control of
hepatic proteolysis by amino acids: the role of cell volume. Eur
J Biochem 1991; 197: 717–724
Lang F, Stehle T, Häussinger D. Water, K+, H+, lactate and
glucose fluxes during cell volume regulation in perfused rat liver.
Pflügers Arch 1989; 413: 209–216
Meijer AJ, Baquet A, Gustafson L, van Woerkom GM, Hue L.
Mechanism of activation of liver glycogen synthase by swelling.
J Biol Chem 1992; 267: 5823–5828
Peak M, Al-Habouri M, Agius L. Regulation of glycogen
synthesis and glycolysis by insulin, pH and cell volume. Biochem
J 1992; 282: 797–805
Saha N, Stoll B, Lang F, Häussinger D. Effect of anisotonic
cell-volume modulation on glutathione-S-conjugate release, tbutylhydroperoxide metabolism and the pentose-phosphate
shunt in perfused rat liver. Eur J Biochem 1992; 209: 437–444
Saha N, Schreiber R, vom Dahl S, Lang F, Gerok W,
Häussinger D. Endogenous hydroperoxide formation, cell
volume and cellular K+ balance in perfused rat liver. Biochem
J 1993; 296: 701–707
Häussinger D, Lang F, Bauers K, Gerok W. Control of hepatic
nitrogen metabolism and gluthatione release by cell volume
regulatory mechanisms. Eur J Biochem 1990; 193: 891–898
Häussinger D, Stoll B, Morimoto Y, Lang F, Gerok W.
Anisoosmotic liver perfusion: redox shifts and modulation of aketiosocaproate and glycine metabolism. Biol Chem HoppeSeyler 1992; 373: 723–734
Häussinger D, Lang F. Exposure of perfused liver to hypotonic
conditions modifies cellular nitrogen metabolism. J Cell Biochem
1990; 43: 355–361
Baquet A, Lavoinne A, Hue L. Comparison of the effects of
various amino acids on glycogen synthesis, lipogenesis and
ketogenesis in isolated rat hepatocytes. Biochem J 1991; 273:
57–62
Häussinger D, Newsome W, vom Dahl S, Stoll B, Noe B,
Schreiber R, Wettstein M, Lang F. Control of liver cell function
by the hydration state. Biochem Soc Trans 1994; 22: 497–502
McCarty NA, O’Neil RG. Calcium signaling in cell volume
regulation. Physiol Rev 1992; 72: 1037–1061
Häussinger D, Stoll B, vom Dahl S, Theodoropoulos PA,
Markogiannakis E, Gravanis A, Lang F, Stournaras C. Effect
of hepatocyte swelling on microtubule stability and tubulin
mRNA levels. Biochem Cell Biol 1994; 72: 12–19
Theodoropoulos T, Stournaras C, Stoll B, Markogiannakis E,
Lang F, Gravanis A, Häussinger D. Hepatocyte swelling leads
to rapid decrease of G-/total actin ratio and increases actin
mRNA levels. FEBS Lett 1992; 311: 241–245
Busch GL, Schreiber R, Dartsch PC, Völkl H, vom Dahl S,
Häussinger D, Lang F. Involvement of microtubules in the link
between cell volume and pH of acidic cellular compartments.
Proc Natl Acad Sci 1994; 91: 9165–9169
Häussinger D, Saha N, Hallbrucker C, Lang F, Gerok W.
Involvement of microtubules in the swelling-induced stimulation
of transcellular taurocholate transport in perfused rat liver.
Biochem J 1993; 291: 355–360
Lang F, Busch GL, Völkl H, Häussinger D. Lysosomal pH—a
link between cell volume and metabolism. Biochem Soc Trans
1994; 22: 502–504
Waldegger S, Raber G, Barth P, Lang F. Regulation of a
putative serine/threonine kinase by cell volume. Proc Natl Acad
Sci USA 1997; (in press)
Völkl H, Rehwald W, Waitz W, Häussinger D, Lang F. Acridine
orange fluorescence in renal proximal tubules: effects of NH /
3
NH+ and cell volume. Cell Physiol Biochem 1993; 3: 28–33
4
Völkl H, Friedrich F, Häussinger D, Lang F. Effect of cell
873
43.
44.
45.
46.
47.
48.
49.
50.
51.
52.
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
volume on Acridine Orange fluorescence in hepatocytes. Biochem
J 1993; 295: 11–14
Mortimore GE, Pösö AR. Intracellular protein catabolism and
its control during nutrient deprivation and supply. Annu Rev
Nutr 1987; 7: 539–564
Busch GL, Guenther E, Hewig B, Zrenner E, Lang F. Effect of
cell swelling, NH Cl and glutamate on acridine orange fluores4
cence in retinal ganglion cells. Cell Physiol Biochem 1996;
6: 185–194
Busch GL, Völkl H, Haller T, Ritter M, Siemen D, Moest J,
Koch F, Lang F. Vesicular pH is sensitive to changes in cell
volume. Cell Physiol Biochem 1997; (in press)
Burg MB, Kwon ED, Kultz D. Osmotic regulation of gene
expression. FASEB J 1996; 10: 1598–1606
Lang F, Busch GL, Gulbins E. Physiology of cell survival and
cell death: Implications for organ conservation. Nephrol Dial
Transplant 1995; 10: 1551–1555
Bianchini L, Grinstein S. Regulation of volume-modulating ion
transport systems by growth promoters. In: Lang F,
Häussinger D, eds Heidelberg, Advances in comparative and
environmental physiology, Springer-Verlag; Berlin, vol. 14,
1993; 249–277
Lang F, Ritter M, Wöll E, Weiss H, Häussinger D, Hoflacher J,
Maly K, Grunicke H. Altered cell volume regulation in ras
oncogene expressing NIH fibroblasts. Pflügers Arch 1992; 420:
424–427
Counillon L, Pouysségur J. Structure, function and growth
factor activation of the Na+/H+ antiporter (NHE1). Cell
Physiol Biochem 1992; 2: 138–149
Nelson N, Beltran C, Supek F, Nelson H. Cell biology and
evolution of proton pumps. Cell Physiol Biochem 1992; 2:
150–158
Gillies RJ, Martinez-Zaguilan R, Peterson EP, Perona R. Role
of intracellular pH in mammalian cell proliferation. Cell Physiol
Biochem 1992; 2: 159–179
Oberleithner H. Endogenous pH oscillations in transformed
epithelial cells. Cell Physiol Biochem 1992; 2: 180–188
Jiang L-W, Maher VM, McCormick JJ, Schindler M.
Alkalinization of the lysosomes is correlated with ras transformation of murine and human fibroblasts. J Biol Chem 1990; 265:
4775–4777
Howard RL, Bichet DG, Schrier RW. Hypernatremic and
polyuric states. In: The kidney: physiology and pathophysiology
(Second Edn), Seldin DW, Giebisch G, eds Raven Press: New
York, 1992: 1753–1778
Bichet DG, Kluge R, Howard RL, Schrier RW. Hyponatremic
states. In: The kidney: physiology and pathophysiology (Second
edn), Seldin DW, Giebisch G. Raven Press: New York, 1992;
1727–1751
Arieff AI, Kleeman CR. Cerebral edema in diabetic comas. II.
Effects of hyperosmolarity, hyperglycemia and insulin in diabetic
rabbits. J Clin Endocrinol Metab 1974; 38: 1057–1067
Sterns RH, Riggs JE, Schochet SS. Osmotic demyelination
syndrome following correction of hyponatremia. New Engl J
Med 1986; 314: 1535–1542
Sterns RH, Thomas DJ, Herndon RM. Brain dehydration and
neurologic deterioration after rapid correction of hypernatremia.
Kidney Int 1989; 35: 69–75
Soupart A, Decaux G. Therapeutic recommendations for management of severe hyponatremia: Current concepts on pathogenesis and prevention of neurologic complications. Clin Nephrol
1996; 46: 149–169
Norenberg MD. Astrocyte responses to CNS injury. J
Neuropathol Exp Neurol 1994; 53: 213–220
Norenberg MD, Bender AS. Astrocyte swelling in liver failure:
Role of glutamine and benzodiazepines. Acta Neurochir 1994;
60: 24–27
Cordoba J, Gottsstein J, Blei AT. Glutamine, myoinositol, and
organic brain osmolytes after portacaval anastomosis in the rat:
Implications for ammonia induced brain edema. Hepatology
1996; 24: 919–923
Kreis R, Farrow N, Ross BD. Localized 1H-NMR spectroscopy
in patients with chronic hepatic encephalopathy. Analysis of
874
65.
66.
67.
68.
69.
S. Waldegger et al.
changes in cerebral glutamine, choline and inositols. NMR
Biomed 1991; 4: 109–116
Burg MB, Kador PF. Sorbitol, osmoregulation, and the complications of diabetes. J Clin Invest 1988; 81: 635–640
Sebekova K, Ling H, Schinzel R, Simm A, Daemmrich J,
Schenk O, Vamvakas S, Heidland A. Potential role of advanced
glycated albumin in the induction of renal hypertrophy: studies
on LLC-PK1 cells. Kidney Blood Press Res 1996; 19: 347–394
Demerdash TM, Seyrek N, Smogorzewski M, Marcinkowski W,
Nassermoadelli S, Massry SG. Pathways through which glucose
induces a rise in [Ca2+] of polymorphonuclear leukocytes of
i
rats. Kidney Int 1996; 50: 2032–2040
Ling H, Vamvakas S, Busch GL, Kulzer P, Schramm L,
Teschner M, Lang F, Heidland A. Suppressing role of transforming growth factor-b1 on cathepsin activity in cultured tubule
cells. Am J Physiol 1995; 269: F911–F917
Ling H, Vamvakas S, Gekle M, Schaefer L, Teschner M,
70.
71.
72.
73.
74.
Schaefer RM, Heidland A. Role of lysosomal cathepsin activities
in cellular hypertrophy induced by NH Cl in cultured tubule
cells. J Am Soc Nephrol 1995; 6: 1021 4
Morocutti A, Earle KA, Rodemann HP, Viberti GC. Premature
cell ageing and evolution of diabetic nephropathy. Diabetologia
1997; 40: 244–246
Hallbrucker C, Vom Dahl S, Ritter M, Lang F, Häussinger D.
Effects of urea on K+ fluxes and cell volume in perfused rat
liver. Pflügers Arch 1994; 428: 552–560
Leviel F, Froissart M, Soualmia H, Poggioli J, Paillard M,
Bichara M. Control of H(+)-HCO - plasma membrane trans3 medullary thick ascending
porters by urea hyperosmolality in rat
limb. Am J Physiol 1994; 266: C1157–C1164
Parker JC. Urea alters set point volume for K-Cl cotransport,
Na-H exchange, and Ca-Na exchange in dog red blood cells.
Am J Physiol 1993; 265: C447–C452
Lee JA, Lee HA, Sadler PJ. Uraemia: is urea more important
than we think? Lancet 1991; 338: 1438–1440